scholarly journals Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives

2020 ◽  
Vol 117 (27) ◽  
pp. 16009-16018 ◽  
Author(s):  
Ling Zou ◽  
Peter Spanogiannopoulos ◽  
Lindsey M. Pieper ◽  
Huan-Chieh Chien ◽  
Wenlong Cai ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Azo Dye ◽  
Pharmacokinetic Studies ◽  
Unintended Effects ◽  
Drug Products ◽  
Intestinal Drug Absorption ◽  
High Concentrations ◽  
Gut Microbial Community ◽  
Selection Of

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R−N=N−R′) dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.

scholarly journals Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives

2019 ◽  
Author(s):  
Ling Zou ◽  
Peter Spanogiannopoulos ◽  
Huan-Chieh Chien ◽  
Lindsey M. Pieper ◽  
Wenlong Cai ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Drug Absorption ◽  
Azo Dye ◽  
Bacterial Metabolism ◽  
Pharmacokinetic Studies ◽  
Unintended Effects ◽  
Human Gut ◽  
Intestinal Drug Absorption ◽  
Transport Inhibitors ◽  
Potential Impact

AbstractFood and drugs contain diverse small molecule additives (excipients) with unclear impacts on human physiology. Here, we evaluate their potential impact on intestinal absorption, screening 136 unique compounds for inhibition of the key transporter OATP2B1. We identified and validated 24 potent OATP2B1 transport inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or non-inhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R−N=N−R′) dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient, inhibited drug absorption; however, the human gut microbiome inactivated azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine.One Sentence SummaryFood and drug additives inhibit intestinal drug transporters, although some are inactivated by gut bacterial metabolism.

scholarly journals The Advantages of the Ussing Chamber in Drug Absorption Studies

2005 ◽  
Vol 10 (5) ◽  
pp. 517-523 ◽  
Author(s):  
Yasumasa Gotoh ◽  
Noboru Kamada ◽  
Denichi Momose
Keyword(s):  
Small Intestine ◽  
Membrane Permeability ◽  
Drug Absorption ◽  
Ussing Chamber ◽  
In Vivo Studies ◽  
Glycoprotein P ◽  
Absorption Studies ◽  
High Concentrations ◽  
Absorption Percentage

By adding high concentrations of test drugs to an Ussing chamber with rat jejunum, we established a systemthat yields very high correlations between the rat absorption percentage and the membrane permeability, and that can accurately predict the absorption percentage for rats. An advantage of this technique is that, unlike the results obtained using Caco-2, the slope of the absorption/membrane-permeability curve is gentle, which facilitates a more exact prediction of the absorption percentage. In addition, the results obtained with this technique demonstrated that it could be used to evaluate the absorption percentage of drugs with an affinity for P-glycoprotein (P-gp), which cannot be assessed using Caco-2. Thismethod also allows for cassette screening, whichwould facilitate evaluation of the contribution of P-gp to absorption in the small intestine. Cassette screening showed that absorption of fexofenadinewas unaffected by combinationwith the P-gp substrate ketoconazole. Consistent with this finding, in vivo studies showed that ketoconazole did not affect the Fa Fg for fexofenadine, a pharmacokinetic parameter that reflects absorption and bioavailability in the small intestine. This confirms the usefulness of the Ussing chamber for cassette screening and also suggests that intestinal P-gp has a minimal contribution to drug absorption.

scholarly journals Alleviation of Nitric Oxide-induced Flower Abscission and Leaf Toxicity in Phlox by Sucrose and 1-MCP

HortScience ◽  
2004 ◽  
Vol 39 (4) ◽  
pp. 823B-823
Author(s):  
Narendra Sankhla ◽  
Wayne Mackay* ◽  
Tim Davis
Keyword(s):  
Nitric Oxide ◽  
Fruits And Vegetables ◽  
Cut Flower ◽  
Flower Buds ◽  
Phlox Paniculata ◽  
Postharvest Life ◽  
High Concentrations ◽  
Flower Abscission ◽  
Selection Of

Low concentration fumigation with nitric oxide (NO*) has been shown to extend the postharvest life of a range of flowers, fruits and vegetables by down-regulating ethylene production. Since ethylene is involved in flower abscission and leaf senescence of `John Fanick' phlox cut flower heads, a superior selection of perennial phlox (Phlox paniculata L.) bearing attractive long-lasting flowers, we have evaluated the effect of NO* delivered in vivo using sodium nitroprusside (SNP) as the source of NO* donor, on postharvest performance of `John Fanick' phlox flower heads. Although the presence of SNP (10-200 μmol·L-1) in the vase solution promoted the abscission of the open flowers, the young flower buds continued to open even in the presence of high SNP concentrations. On the other hand, at high SNP concentrations, the leaves became either yellow, or more frequently turned progressively black and senesced. Inclusion of sucrose in the vase solution, or pretreatment of flower heads with either 1-MCP or STS, significantly delayed the abscission of flowers and blackening of leaves. The pretreatment of flower heads with either 1-MCP or STS, or the presence of sucrose in the vase, together with SNP, greatly reduced the toxicity of the latter chemical resulting in improved postharvest display life. These results indicate that in `John Fanick' the leaves are relatively more susceptible to NO*-induced toxicity than the flowers. However, both sucrose and ethylene perception inhibitors are able to minimize the toxicity of high concentrations of NO* delivered in vivo via SNP.

scholarly journals Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches

Pharmaceutics ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 411 ◽  
Author(s):  
David Dahlgren ◽  
Hans Lennernäs
Keyword(s):  
Intestinal Permeability ◽  
Drug Absorption ◽  
Pharmaceutical Products ◽  
Physiological Factors ◽  
Drug Products ◽  
Absorption Models ◽  
Gi Absorption ◽  
Multiple Interactions

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value Peff) has been widely used to determine the rate and extent of the drug’s intestinal absorption (Fabs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting Fabs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal Peff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes.

In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations

2017 ◽  
Vol 14 (12) ◽  
pp. 4233-4242 ◽  
Author(s):  
Carl Roos ◽  
David Dahlgren ◽  
Staffan Berg ◽  
Jan Westergren ◽  
Bertil Abrahamsson ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Intestinal Drug Absorption

Hair cell changes after cationic stimulation of corti's organ

1989 ◽  
Vol 47 ◽  
pp. 798-799
Author(s):  
Cesar D. Fermin ◽  
Hans-Peter Zenner
Keyword(s):  
Organ Of Corti ◽  
Cross Sectional ◽  
Surface Areas ◽  
High K ◽  
Anatomical Arrangement ◽  
Cell Cytosol ◽  
High Concentrations ◽  
K Concentration ◽  
Cell Changes

Contraction of outer and inner hair cells (OHC&IHC) in the Organ of Corti (OC) of the inner ear is necessary for sound transduction. Getting at HC in vivo preparations is difficult. Thus, isolated HCs have been used to study OHC properties. Even though viability has been shown in isolated (iOHC) preparations by good responses to current and cationic stimulation, the contribution of adjoining cells can not be explained with iOHC preparations. This study was undertaken to examine changes in the OHC after expossure of the OHC to high concentrations of potassium (K) and sodium (Na), by carefully immersing the OC in either artifical endolymph or perilymph. After K and Na exposure, OCs were fixed with 3% glutaraldehyde, post-fixed in osmium, separated into base, middle and apex and embedded in Araldite™. One μm thick sections were prepared for analysis with the light and E.M. Cross sectional areas were measured with Bioquant™ software.Potassium and sodium both cause isolated guinea pig OHC to contract. In vivo high K concentration may cause uncontrolled and sustained contractions that could contribute to Meniere's disease. The behavior of OHC in the vivo setting might be very different from that of iOHC. We show here changes of the cell cytosol and cisterns caused by K and Na to OHC in situs. The table below shows results from cross sectional area measurements of OHC from OC that were exposed to either K or Na. As one would expect, from the anatomical arrangement of the OC, OHC#l that are supported by rigid tissue would probably be displaced (move) less than those OHC located away from the pillar. Surprisingly, cells in the middle turn of the cochlea changed their surface areas more than those at either end of the cochlea. Moreover, changes in surface area do not seem to differ between K and Na treated OCs.

A Multicenter Study of Recombinant Factor VIII (RecombinateTM) in Previously Treated Patients with Hemophilia A

1997 ◽  
Vol 77 (04) ◽  
pp. 660-667 ◽  
Author(s):  
G C White ◽  
S Courter ◽  
G L Bray ◽  
M Lee ◽  
E D Gomperts ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Dna ◽  
Home Treatment ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Treat Ment ◽  
Previously Treated Patients ◽  
Bleeding Episodes

SummaryA prospective, open-label multicenter investigation has been conducted to compare pharmacokinetic parameters of recombinant DNA-derived FVIII (rFVIII) and plasma-derived FVIII concentrate (pdFVIII) and to assess safety and efficacy of long-term home-treat- ment with rFVIII for subjects with hemophilia A. Following comparative in vivo pharmacokinetic studies, 69 patients with severe (n = 67) or moderate (n = 2) hemophilia A commenced a program of home treatment using rFVIII exclusively for prophylaxis and treatment of all bleeding episodes for a period of 1.0 to 5.7 years (median 3.7 years). The mean in vivo half-lives of rFVIII and pdFVIII were both 14.7 h. In vivo incremental recoveries at baseline were 2.40%/IU/kg and 2.47%/IU/kg, respectively (p = 0.59). The response to home treatment with rFVIII was categorized as good or excellent in 3,195 (91.2%) of 3,481 evaluated bleeding episodes. Thirteen patients received rFVIII for prophylaxis for twenty-four surgical procedures. In all cases, hemostasis was excellent. Adverse reactions were observed in only 13 of 13,591 (0.096%) infusions of rFVIII; none was serious. No patient developed an inhibitor to r FVIII.

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